ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS. Medicinal product no longer authorised

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1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1

2 1. NAME OF THE MEDICINAL PRODUCT Prevenar suspension for injection Pneumococcal saccharide conjugated vaccine, adsorbed 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each 0.5 ml dose contains: Pneumococcal polysaccharide serotype 4* Pneumococcal polysaccharide serotype 6B* Pneumococcal polysaccharide serotype 9V* Pneumococcal polysaccharide serotype 14* Pneumococcal polysaccharide serotype 18C* Pneumococcal polysaccharide serotype 19F* Pneumococcal polysaccharide serotype 23F* 2 micrograms 4 micrograms 2 micrograms 2 micrograms 2 micrograms 2 micrograms 2 micrograms * Conjugated to the CRM 197 carrier protein and adsorbed on aluminium phosphate (0.5 mg) For a full list of excipients, see section PHARMACEUTICAL FORM Suspension for injection. The vaccine is a homogeneous white suspension. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Active immunisation against disease caused by Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F and 23F (including sepsis, meningitis, pneumonia, bacteraemia and acute otitis media) in infants and children from 2 months up to 5 years of age (see sections 4.2, 4.4 and 5.1). For the number of doses to be administered in the different age groups, see section 4.2. The use of Prevenar should be determined on the basis of official recommendations taking into consideration the impact of invasive disease in different age groups as well as variability of serotype epidemiology in different geographical areas (see sections 4.4, 4.8 and 5.1). 4.2 Posology and method of administration Posology The immunisation schedules for Prevenar should be based on official recommendations. Infants aged 2-6 months: The primary infant series consists of three doses, each of 0.5 ml, the first dose usually given at 2 months of age and with an interval of at least 1 month between doses. A fourth dose is recommended in the second year of life. 2

3 Alternatively, when Prevenar is given as part of a routine infant immunisation programme, a two-dose schedule may be considered. The first dose may be given from the age of 2 months with a second dose at least 2 months later and a third (booster) dose at months of age (see section 5.1) Previously unvaccinated older infants and children: Infants aged 7-11 months: two doses, each of 0.5 ml, with an interval of at least 1 month between doses. A third dose is recommended in the second year of life. Children aged months: two doses, each of 0.5 ml, with an interval of at least 2 months between doses. Children aged 24 months 5 years: one single dose. The need for a booster dose after these immunisation schedules has not been established. Method of administration The vaccine should be given by intramuscular injection. The preferred sites are anterolateral aspect of the thigh (vastus lateralis muscle) in infants or the deltoid muscle of the upper arm in young children. 4.3 Contraindications Hypersensitivity to the active substances or to any of the excipients, or to diphtheria toxoid. As with other vaccines, the administration of Prevenar should be postponed in subjects suffering from acute, severe febrile illness. However, the presence of a minor infection, such as a cold, should not result in the deferral of vaccination. 4.4 Special warnings and precautions for use As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic event following the administration of the vaccine. Do not administer Prevenar intravenously. The potential risk of apnoea and the need for respiratory monitoring for 48-72h should be considered when administering the primary immunisation series to very premature infants (born 28 weeks of gestation) and particularly for those with a previous history of respiratory immaturity. As the benefit of vaccination is high in this group of infants, vaccination should not be withheld or delayed. Prevenar will not protect against other Streptococcus pneumoniae serotypes than those included in the vaccine nor other micro-organisms that cause invasive disease or otitis media. This vaccine should not be given to infants or children with thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injection unless the potential benefit clearly outweighs the risk of administration. Although some antibody response to diphtheria toxoid may occur, immunisation with this vaccine does not substitute for routine diphtheria immunisation. For children from 2 years through 5 years of age, a single dose immunisation schedule was used. A higher rate of local reactions has been observed in children older than 24 months of age compared with infants (see section 4.8). Children with impaired immune responsiveness, whether due to the use of immunosuppressive therapy, a genetic defect, HIV infection, or other causes, may have reduced antibody response to active immunisation. 3

4 Limited data have demonstrated that Prevenar (three dose primary series) induces an acceptable immune response in infants with sickle cell disease with a safety profile similar to that observed in non-high-risk groups (see section 5.1). Safety and immunogenicity data are not yet available for children in other specific high-risk groups for invasive pneumococcal disease (e.g. children with another congenital or acquired splenic dysfunction, HIV-infected, malignancy, nephrotic syndrome). Vaccination in high-risk groups should be considered on an individual basis. Children below 2 years old should receive the appropriate-for-age Prevenar vaccination series (see section 4.2). The use of pneumococcal conjugate vaccine does not replace the use of 23-valent pneumococcal polysaccharide vaccines in children 24 months of age with conditions (such as sickle cell disease, asplenia, HIV infection, chronic illness or who are immunocompromised) placing them at higher risk for invasive disease due to Streptococcus pneumoniae. Whenever recommended, children at risk who are 24 months of age and already primed with Prevenar should receive 23-valent pneumococcal polysaccharide vaccine. The interval between the pneumococcal conjugate vaccine (Prevenar) and the 23- valent pneumococcal polysaccharide vaccine should not be less than 8 weeks. There are no data available to indicate whether the administration of 23-valent pneumococcal polysaccharide vaccine to unprimed children or to children primed with Prevenar might result in hyporesponsiveness to further doses of Prevenar. When Prevenar is co-administered with hexavalent vaccines (DTaP/Hib(PRP-T)/IPV/HepB), the physician should be aware that data from clinical studies indicate that the rate of febrile reactions was higher compared to that occurring following the administration of hexavalent vaccines alone. These reactions were mostly moderate (less than or equal to 39 C) and transient (see section 4.8). Antipyretic treatment should be initiated according to local treatment guidelines. Prophylactic antipyretic medication is recommended: - for all children receiving Prevenar simultaneously with vaccines containing whole cell pertussis because of higher rate of febrile reactions (see section 4.8). - for children with seizure disorders or with a prior history of febrile seizures. As with any vaccine, Prevenar may not protect all individuals receiving the vaccine from pneumococcal disease. Additionally, for vaccine serotypes, protection against otitis media is expected to be substantially lower than protection against invasive disease. As otitis media is caused by many organisms other than pneumococcal serotypes represented in the vaccine, protection against all otitis media is expected to be low (see section 5.1). 4.5 Interaction with other medicinal products and other forms of interaction Prevenar can be administered simultaneously with other paediatric vaccines in accordance with the recommended immunisation schedules. Different injectable vaccines should always be given at different injection sites. The immune response to routine paediatric vaccines co-administered with Prevenar at different injection sites was assessed in 7 controlled clinical studies. The antibody response to Hib tetanus protein conjugate (PRP-T), tetanus and Hepatitis B (HepB) vaccines was similar to controls. For CRM-based Hib conjugate vaccine, enhancement of antibody responses to Hib and diphtheria in the infant series was observed. At the booster, some suppression of Hib antibody level was observed but all children had protective levels. Inconsistent reduction in response to pertussis antigens as well as to inactivated polio vaccine (IPV) were observed. The clinical relevance of these interactions is unknown. Limited results from open label studies showed an acceptable response to MMR and varicella. 4

5 Data on concomitant administration of Prevenar with Infanrix hexa (DTaP/Hib(PRP-T)/IPV/HepB vaccine) have shown no clinically relevant interference in the antibody response to each of the individual antigens when given as a 3 dose primary vaccination. Sufficient data regarding interference on the concomitant administration of other hexavalent vaccines with Prevenar are currently not available. In a clinical trial that compared separate with concomitant administrations of Prevenar (three doses at 2, 3.5, 6 months and a booster dose at approximately 12 months) and Meningitec (meningococcal C conjugate vaccine; two doses at 2 and 6 months and a booster dose at approximately 12 months) there was no evidence of immune interference between the two conjugate vaccines after the primary series or after the booster doses. 4.6 Fertility, pregnancy and lactation Prevenar is not intended for use in adults. Human data on the use during pregnancy or lactation and animal reproduction studies are not available. 4.7 Effects on ability to drive and use machines Not relevant. 4.8 Undesirable effects The safety of the vaccine was assessed in different controlled clinical studies in which more than 18,000 healthy infants (6 weeks to 18 months) were included. The majority of the safety experience comes from the efficacy trial in which 17,066 infants received 55,352 doses of Prevenar. Also safety in previously unvaccinated older children has been assessed. In all studies, Prevenar was administered concurrently with the recommended childhood vaccines. Amongst the most commonly reported adverse reactions were injection site reactions and fever. No consistent increased local or systemic reactions within repeated doses were seen throughout the primary series or with the booster dose, the exceptions being a higher rate of transient tenderness (36.5 %) and tenderness that interfered with limb movement (18.5 %) were seen with the booster dose. In older children receiving a single dose of vaccine, a higher rate of local reactions has been observed than that previously described in infancy. These reactions were primarily transient in nature. In a post licensure study involving 115 children between 2-5 years of age, tenderness was reported in up to 39.1 % of children; in 15.7 % of children the tenderness interfered with limb movement. Redness was reported in 40.0 % of children, and induration was reported in 32.2 % of subjects. Redness or induration >2cm in diameter was reported in 22.6 % and 13.9 % of children respectively. When Prevenar is co-administered with hexavalent vaccines (DTaP/Hib(PRP-T)/IPV/HepB), fever 38 C per dose was reported in 28.3 % to 48.3 % of infants in the group receiving Prevenar and the hexavalent vaccine at the same time as compared to 15.6 % to 23.4 % in the group receiving the hexavalent vaccine alone. Fever of greater than 39.5 C per dose was observed in 0.6 to 2.8 % of infants receiving Prevenar and hexavalent vaccines (see section 4.4). Reactogenicity was higher in children receiving whole cell pertussis vaccines concurrently. In a study, including 1,662 children, fever of 38 C was reported in 41.2 % of children who received Prevenar simultaneously with DTP as compared to 27.9 % in the control group. Fever of > 39 C was reported in 3.3 % of children compared to 1.2 % in the control group. 5

6 Adverse reactions reported in clinical trials or from the post-marketing experience are listed in the following table per system organ class and per frequency and this is for all age groups. The frequency is defined as follows: Very common( 1/10) Common ( 1/100 to < 1/10) Uncommon ( 1/1,000 to < 1/100) Rare ( 1/10,000 to < 1/1,000) Very rare (< 1/10,000) Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Blood and lymphatic system disorders: Very rare: Lymphadenopathy localised to the region of the injection site Immune system disorders: Rare: Hypersensitivity reactions such as anaphylactic/anaphylactoid reactions including shock, angioneurotic oedema, bronchospasm, dyspnoea, face oedema. Nervous system disorders: Rare: Seizures, including febrile seizures. Gastrointestinal disorders: Very common: Vomiting, diarrhoea, decreased appetite. Skin and subcutaneous tissue disorders: Uncommon: Rash/urticaria. Very rare: Erythema multiforme. General disorders and administration site conditions: Very common: Injection site reactions (e.g. erythema, induration/swelling, pain/tenderness); fever 38 C, irritability, crying, drowsiness, restless sleep. Common: Injection site swelling/induration and erythema >2.4 cm, tenderness interfering with movement, fever > 39 C. Rare: Hypotonic hyporesponsive episode, injection site hypersensitivity reactions (eg., dermatitis, pruritus, urticaria), flushing. Apnoea in very premature infants ( 28 weeks of gestation) (see section 4.4). 4.9 Overdose There have been reports of overdose with Prevenar, including cases of administration of a higher than recommended dose and cases of subsequent doses administered closer than recommended to the previous dose. No undesirable effects were reported in the majority of individuals. In general, adverse reactions reported with overdose have also been reported with recommended single doses of Prevenar. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: pneumococcal vaccines, ATC code: J07AL02 6

7 Immunogenicity Significant increases in antibody (measured by ELISA) were seen for all vaccine serotypes following a three-dose primary series of Prevenar in infants and following booster doses although geometric mean concentrations varied between the 7 serotypes. Prevenar has also been shown to elicit functional antibodies (measured by opsonophagocytosis) to all vaccine serotypes following the primary series. Longterm persistence of antibodies has not been investigated after administration of a primary series in infants plus booster or after administration of single priming doses to older children. Administration of unconjugated pneumococcal polysaccharides at 13 months following the primary series with Prevenar elicited an anamnestic antibody response for the 7 serotypes included in the vaccine, indicating that priming had occurred. The immunogenicity of a two-dose primary series in infants plus a booster at about one year of age has been documented in several studies. Most of the data have indicated that smaller proportions of infants achieved antibody concentrations 0.35 μg/ml (the reference antibody concentration recommended by WHO) 1 against serotypes 6B and 23F after two-dose primary series when directly or indirectly compared with three-dose primary series. In addition, GMCs were lower for antibodies to most serotypes after a twodose infant series than after a three-dose infant series. However, antibody responses to booster doses in toddlers following two-dose or three-dose infant series were comparable for all 7 vaccine serotypes and indicated that both infant regimens had elicited adequate priming. Significant increases in antibody (measured by ELISA) to all vaccine serotypes were seen after administration of single doses of Prevenar to children aged 2 to 5 years. Antibody concentrations were similar to those achieved following a three-dose infant series and a booster dose at less than 2 years of age. Efficacy trials in the 2- to 5-year-old population have not been conducted. Clinical trial efficacy of the two-dose infant primary series plus a booster has not been established, and the clinical consequences of lower antibody concentrations against serotypes 6B and 23F after the two-dose infant series are not known. Efficacy against invasive disease Estimates of efficacy against invasive disease were obtained in the US population where vaccine serotype coverage ranged from 80 to 89 %. Epidemiological data between 1988 and 2003 indicated that in Europe coverage is lower and varies from country to country. Consequently, Prevenar should cover between 54 % and 84 % of isolates from invasive pneumococcal disease (IPD) in European children less than 2 years of age. In European children between 2 to 5 years of age, Prevenar should cover about 62 % to 83 % of the clinical isolates responsible for invasive pneumococcal disease. It is estimated that more than 80 % of the antimicrobial resistant strains would be covered by the serotypes included in the vaccine. The vaccine serotype coverage in the paediatric population decreases with increasing age. The decrease in the incidence of IPD seen in older children may be partly due to naturally acquired immunity. Efficacy against invasive disease was assessed in a large-scale randomised, double-blind, clinical trial in a multiethnic population in Northern California (Kaiser Permanente trial). More than 37,816 infants were immunised with either Prevenar or a control vaccine (meningococcal conjugate group C vaccine), at 2, 4, 6 and months of age. At the time of the study, the serotypes included in the vaccine accounted for 89 % of IPD. A total of 52 cases of invasive disease caused by vaccine serotypes had accumulated in a blinded followup period through April 20, The estimate of vaccine serotype specific efficacy was 94 % (95 % CI: 81, 99) in the intent-to-treat population and 97 % (95 % CI: 85, 100) in the per protocol (fully immunized) population (40 cases). In Europe, the estimates of effectiveness in children less than 2 years of age range from 51 % to 79 % when considering vaccine coverage against serotypes causing invasive disease. 1 WHO technical report No 927, 2005; Appendix serological criteria for calculation and licensure of new pneumococcal conjugate vaccine formulations for use in infants. 7

8 Efficacy against pneumonia In the Kaiser Permanente trial, efficacy was 87.5 % (95 % CI: 7, 99) against bacteraemic pneumonia due to vaccine serotypes of S. pneumoniae. Effectiveness (no microbiological confirmation of diagnosis was performed) against non-bacteraemic pneumonia was also assessed. As many pathogens other than pneumococcal serotypes represented in the vaccine may contribute to the burden of pneumonia in children, protection against all clinical pneumonia is expected to be lower than for invasive pneumococcal disease. In the per-protocol analysis, the estimated risk reduction for the first episode of clinical pneumonia with abnormal chest radiograph (defined as the presence of infiltrates, effusion or consolidation) was 35 % (95 % CI: 4, 56). Efficacy against otitis media Acute otitis media (AOM) is a common childhood disease with different aetiologies. Bacteria can be responsible for 60-70% of clinical episodes of AOM. The pneumococcus is responsible for 30-40% of all bacterial AOM and a greater fraction of severe AOM. Theoretically, Prevenar could prevent about 60-80% of serotypes causing pneumococcal AOM. It is estimated that Prevenar could prevent 6-13% of all clinical episodes of AOM. Efficacy of Prevenar against acute otitis media (AOM) was assessed in a randomised, double blind, clinical trial of 1,662 Finnish infants immunised with either Prevenar or a control vaccine (Hepatitis B vaccine), at 2, 4, 6 and months of age. The estimate for vaccine efficacy against vaccine-serotype AOM, the primary endpoint of the trial, was 57 % (95 % CI: 44, 67) in the per-protocol analysis and 54 % (95 % CI: 41, 64) in the intent-to-treat analysis. A 33 % (95 % CI: -1, 80) increase in AOM due to serogroups not included in the vaccine was observed in immunised subjects. However, the overall benefit was a 34 % (95 % CI: 21, 45) reduction in the incidence of all pneumococcal AOM. The impact of the vaccine on total number of episodes of otitis media regardless of etiology was a 6 % (95 % CI: -4, 16) reduction. A subset of children in this study were followed until they reached 4 to 5 years of age. In this follow-up, vaccine efficacy for frequent OM (defined as at least 3 episodes within 6 months) was 18 % (95 % CI: 1, 32), for chronic otitis media with effusion, 50 % (95 % CI: 15, 71), and for tympanostomy tube placement, 39 % (95 % CI: 4, 61). Efficacy of Prevenar against AOM was assessed as a secondary endpoint in the Kaiser Permanente trial. Children were followed until 3.5 years of age. The impact of the vaccine on total number of episodes of otitis media regardless of etiology was a 7 % reduction (95 % CI: 4, 10). The effect of the vaccine in the per-protocol analysis was a 9 % reduction (95 % CI: 3, 15) in recurrent AOM (defined as 3 episodes in six months or 4 episodes in one year) or a 23 % (95 % CI: 7, 36) reduction for recurrent AOM (5 episodes in six months or 6 episodes in one year). Tympanostomy tube placement was reduced by 24 % (95 % CI: 12, 35) in the per-protocol analysis and by 23 % (95 % CI: 11, 34) in the intent-to-treat analysis. Effectiveness The effectiveness of Prevenar against IPD (i.e. comprising the protection afforded by vaccination and from herd immunity due to reduced transmission of vaccine serotypes in the population) has been evaluated in national immunisation programmes that employ three-dose or two-dose infant series, each with booster doses. In the USA, generalised vaccination with Prevenar using a four-dose series in infants and a catch-up programme for children up to 5 years of age was introduced in Vaccine effectiveness against IPD caused by vaccine serotypes was evaluated in 3- to 59-month old children within the first four years of the 8

9 implementation of the programme. When compared with no vaccination, point estimates for the effectiveness of 2-, 3-, or 4-doses given on an infant schedule were similar: 96% (95% CI 88-99); 95% (95% CI 88-99); and 100% (95% CI ), respectively. In the USA in the same time frame, there was a 94% reduction in vaccine type IPD in individuals under 5 years of age, compared to a pre-vaccine baseline (1998/99). In parallel, there was a 62% reduction in vaccine type IPD in individuals over 5 years of age. This indirect or herd effect is due to a reduction in transmission of vaccine serotypes from immunised young children to the rest of the population and coincides with decreased nasopharyngeal carriage of vaccine serotypes. In Quebec, Canada Prevenar was introduced at 2, 4 and 12 months of age with a single dose catch-up programme in children up to 5 years of age. In the first two years of the programme, with over 90% coverage, the observed effectiveness against IPD caused by vaccine serotypes was 93% (95% CI 75-98) for the 2 dose infant series and 100% (95% CI ) for the completed schedule. Preliminary data from England and Wales reported less than 1 year following introduction of routine immunisation at 2, 4 and 13 months with a single dose catch-up programme for children 13 to 23 months of age have suggested that effectiveness of this schedule might be lower against serotype 6B than against the other serotypes in the vaccine. The effectiveness of a two-dose primary series has not been established against pneumonia or acute otitis media. Additional immunogenicity data The immunogenicity of Prevenar has been investigated in an open-label, multicenter study in 49 infants with sickle cell disease. Children were vaccinated with Prevenar (3 doses one month apart from the age of 2 months) and 46 of these children also received a 23-valent pneumococcal polysaccharide vaccine at the age of months. After primary immunisation, 95.6% of the subjects had antibody levels of at least 0.35 µg/ml for all seven serotypes found in Prevenar. A significant increase was seen in the concentrations of antibodies against the seven serotypes after the polysaccharide vaccination, suggesting that immunological memory was well established. 5.2 Pharmacokinetic properties Not applicable. 5.3 Preclinical safety data A repeated dose intramuscular toxicity study (13 weeks, 5 injections, one every three weeks) of pneumococcal conjugate vaccine in rabbits revealed no evidence of any significant local or systemic toxic effects. Repeated dose subcutaneous toxicity studies (13 weeks, 7 injections of the clinical dose, one every other week, followed by a 4-week recovery period) of Prevenar in rats and monkeys revealed no evidence of any significant local or systemic toxic effects. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium chloride Water for injections 9

10 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 3 years 6.4 Special precautions for storage Store in a refrigerator (2 C 8 C). Do not freeze. 6.5 Nature and contents of container 0.5 ml suspension for injection in vial (Type I glass) with a grey butyl rubber stopper. Pack sizes: 1 or 10 vials without syringe/needles. 1 vial with syringe and 2 needles (1 for withdrawal, 1 for injection). Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Upon storage, a white deposit and clear supernatant can be observed. The vaccine should be well shaken to obtain a homogeneous white suspension and be inspected visually for any particulate matter and/or variation of physical aspect prior to administration. Do not use if the content appears otherwise. Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Pfizer Limited Ramsgate Road Sandwich Kent CT13 9NJ United Kingdom 8. MARKETING AUTHORISATION NUMBER(S) EU/1/00/167/001 EU/1/00/167/002 EU/1/00/167/005 10

11 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 02/02/2001 Date of last renewal: 02/02/ DATE OF REVISION OF THE TEXT Detailed information on this product is available on the website of the European Medicines Agency 11

12 1. NAME OF THE MEDICINAL PRODUCT Prevenar suspension for injection in pre-filled syringe Pneumococcal saccharide conjugated vaccine, adsorbed 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each 0.5 ml dose contains: Pneumococcal polysaccharide serotype 4* Pneumococcal polysaccharide serotype 6B* Pneumococcal polysaccharide serotype 9V* Pneumococcal polysaccharide serotype 14* Pneumococcal polysaccharide serotype 18C* Pneumococcal polysaccharide serotype 19F* Pneumococcal polysaccharide serotype 23F* 2 micrograms 4 micrograms 2 micrograms 2 micrograms 2 micrograms 2 micrograms 2 micrograms * Conjugated to the CRM 197 carrier protein and adsorbed on aluminium phosphate (0.5 mg) For a full list of excipients, see section PHARMACEUTICAL FORM Suspension for injection in pre-filled syringe. The vaccine is a homogeneous white suspension. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Active immunisation against disease caused by Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F and 23F (including sepsis, meningitis, pneumonia, bacteraemia and acute otitis media) in infants and children from 2 months up to 5 years of age (see sections 4.2, 4.4 and 5.1). For the number of doses to be administered in the different age groups, see section 4.2. The use of Prevenar should be determined on the basis of official recommendations taking into consideration the impact of invasive disease in different age groups as well as variability of serotype epidemiology in different geographical areas (see sections 4.4, 4.8 and 5.1). 4.2 Posology and method of administration Posology The immunisation schedules for Prevenar should be based on official recommendations. Infants aged 2-6 months: The primary infant series consists of three doses, each of 0.5 ml, the first dose usually given at 2 months of age and with an interval of at least 1 month between doses. A fourth dose is recommended in the second year of life. 12

13 Alternatively, when Prevenar is given as part of a routine infant immunisation programme, a two-dose schedule may be considered. The first dose may be given from the age of 2 months with a second dose at least 2 months later and a third (booster) dose at months of age (see section 5.1) Previously unvaccinated older infants and children: Infants aged 7-11 months: two doses, each of 0.5 ml, with an interval of at least 1 month between doses. A third dose is recommended in the second year of life. Children aged months: two doses, each of 0.5 ml, with an interval of at least 2 months between doses. Children aged 24 months 5 years: one single dose. The need for a booster dose after these immunisation schedules has not been established. Method of administration The vaccine should be given by intramuscular injection. The preferred sites are anterolateral aspect of the thigh (vastus lateralis muscle) in infants or the deltoid muscle of the upper arm in young children. 4.3 Contraindications Hypersensitivity to the active substances or to any of the excipients, or to diphtheria toxoid. As with other vaccines, the administration of Prevenar should be postponed in subjects suffering from acute, severe febrile illness. However, the presence of a minor infection, such as a cold, should not result in the deferral of vaccination. 4.4 Special warnings and precautions for use As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic event following the administration of the vaccine. Do not administer Prevenar intravenously. The potential risk of apnoea and the need for respiratory monitoring for 48-72h should be considered when administering the primary immunisation series to very premature infants (born 28 weeks of gestation) and particularly for those with a previous history of respiratory immaturity. As the benefit of vaccination is high in this group of infants, vaccination should not be withheld or delayed. Prevenar will not protect against other Streptococcus pneumoniae serotypes than those included in the vaccine nor other micro-organisms that cause invasive disease or otitis media. This vaccine should not be given to infants or children with thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injection unless the potential benefit clearly outweighs the risk of administration. Although some antibody response to diphtheria toxoid may occur, immunisation with this vaccine does not substitute for routine diphtheria immunisation. For children from 2 years through 5 years of age, a single dose immunisation schedule was used. A higher rate of local reactions has been observed in children older than 24 months of age compared with infants (see section 4.8). 13

14 Children with impaired immune responsiveness, whether due to the use of immunosuppressive therapy, a genetic defect, HIV infection, or other causes, may have reduced antibody response to active immunisation. Limited data have demonstrated that Prevenar (three dose primary series) induces an acceptable immune response in infants with sickle cell disease with a safety profile similar to that observed in non-high-risk groups (see section 5.1). Safety and immunogenicity data are not yet available for children in other specific high-risk groups for invasive pneumococcal disease (e.g. children with another congenital or acquired splenic dysfunction, HIV-infected, malignancy, nephrotic syndrome). Vaccination in high-risk groups should be considered on an individual basis. Children below 2 years old should receive the appropriate-for-age Prevenar vaccination series (see section 4.2). The use of pneumococcal conjugate vaccine does not replace the use of 23-valent pneumococcal polysaccharide vaccines in children 24 months of age with conditions (such as sickle cell disease, asplenia, HIV infection, chronic illness or who are immunocompromised) placing them at higher risk for invasive disease due to Streptococcus pneumoniae. Whenever recommended, children at risk who are 24 months of age and already primed with Prevenar should receive 23-valent pneumococcal polysaccharide vaccine. The interval between the pneumococcal conjugate vaccine (Prevenar) and the 23- valent pneumococcal polysaccharide vaccine should not be less than 8 weeks. There are no data available to indicate whether the administration of 23-valent pneumococcal polysaccharide vaccine to unprimed children or to children primed with Prevenar might result in hyporesponsiveness to further doses of Prevenar. When Prevenar is co-administered with hexavalent vaccines (DTaP/Hib(PRP-T)/IPV/HepB), the physician should be aware that data from clinical studies indicate that the rate of febrile reactions was higher compared to that occurring following the administration of hexavalent vaccines alone. These reactions were mostly moderate (less than or equal to 39 C) and transient (see section 4.8). Antipyretic treatment should be initiated according to local treatment guidelines. Prophylactic antipyretic medication is recommended: - for all children receiving Prevenar simultaneously with vaccines containing whole cell pertussis because of higher rate of febrile reactions (see section 4.8). - for children with seizure disorders or with a prior history of febrile seizures. As with any vaccine, Prevenar may not protect all individuals receiving the vaccine from pneumococcal disease. Additionally, for vaccine serotypes, protection against otitis media is expected to be substantially lower than protection against invasive disease. As otitis media is caused by many organisms other than pneumococcal serotypes represented in the vaccine, protection against all otitis media is expected to be low (see section 5.1). 4.5 Interaction with other medicinal products and other forms of interaction Prevenar can be administered simultaneously with other paediatric vaccines in accordance with the recommended immunisation schedules. Different injectable vaccines should always be given at different injection sites. The immune response to routine paediatric vaccines co-administered with Prevenar at different injection sites was assessed in 7 controlled clinical studies. The antibody response to Hib tetanus protein conjugate (PRP-T), tetanus and Hepatitis B (HepB) vaccines was similar to controls. For CRM-based Hib conjugate vaccine, enhancement of antibody responses to Hib and diphtheria in the infant series was observed. At the booster, some suppression of Hib antibody level was observed but all children had protective levels. Inconsistent reduction in response to pertussis antigens as well as to inactivated polio vaccine (IPV) were 14

15 observed. The clinical relevance of these interactions is unknown. Limited results from open label studies showed an acceptable response to MMR and varicella. Data on concomitant administration of Prevenar with Infanrix hexa (DTaP/Hib(PRP-T)/IPV/HepB vaccine) have shown no clinically relevant interference in the antibody response to each of the individual antigens when given as a 3 dose primary vaccination. Sufficient data regarding interference on the concomitant administration of other hexavalent vaccines with Prevenar are currently not available. In a clinical trial that compared separate with concomitant administrations of Prevenar (three doses at 2, 3.5, 6 months and a booster dose at approximately 12 months) and Meningitec (meningococcal C conjugate vaccine; two doses at 2 and 6 months and a booster dose at approximately 12 months) there was no evidence of immune interference between the two conjugate vaccines after the primary series or after the booster doses. 4.6 Fertility, pregnancy and lactation Prevenar is not intended for use in adults. Human data on the use during pregnancy or lactation and animal reproduction studies are not available. 4.7 Effects on ability to drive and use machines Not relevant. 4.8 Undesirable effects The safety of the vaccine was assessed in different controlled clinical studies in which more than 18,000 healthy infants (6 weeks to 18 months) were included. The majority of the safety experience comes from the efficacy trial in which 17,066 infants received 55,352 doses of Prevenar. Also safety in previously unvaccinated older children has been assessed. In all studies, Prevenar was administered concurrently with the recommended childhood vaccines. Amongst the most commonly reported adverse reactions were injection site reactions and fever. No consistent increased local or systemic reactions within repeated doses were seen throughout the primary series or with the booster dose, the exceptions being a higher rate of transient tenderness (36.5 %) and tenderness that interfered with limb movement (18.5 %) were seen with the booster dose. In older children receiving a single dose of vaccine, a higher rate of local reactions has been observed than that previously described in infancy. These reactions were primarily transient in nature. In a post licensure study involving 115 children between 2-5 years of age, tenderness was reported in 39.1 % of children; in 15.7 % of children the tenderness interfered with limb movement. Redness was reported in 40.0 % of children, and induration was reported in 32.2 % of subjects. Redness or induration >2cm in diameter was reported in 22.6 % and 13.9% of children respectively. When Prevenar is co-administered with hexavalent vaccines (DTaP/Hib(PRP-T)/IPV/HepB), fever 38 C per dose was reported in 28.3 % to 48.3 % of infants in the group receiving Prevenar and the hexavalent vaccine at the same time as compared to 15.6 % to 23.4 % in the group receiving the hexavalent vaccine alone. Fever of greater than 39.5 C per dose was observed in 0.6 to 2.8 % of infants receiving Prevenar and hexavalent vaccines (see section 4.4). Reactogenicity was higher in children receiving whole cell pertussis vaccines concurrently. In a study, including 1,662 children, fever of 38 C was reported in 41.2 % of children who received Prevenar 15

16 simultaneously with DTP as compared to 27.9 % in the control group. Fever of > 39 C was reported in 3.3 % of children compared to 1.2 % in the control group. Adverse reactions reported in clinical trials or from the post-marketing experience are listed in the following table per system organ class and per frequency and this is for all age groups. The frequency is defined as follows: Very common ( 1/10) Common ( 1/100 to < 1/10) Uncommon ( 1/1,000 to < 1/100) Rare ( 1/10,000 to < 1/1,000) Very rare (< 1/10,000) Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness Blood and lymphatic system disorders: Very rare: Lymphadenopathy localised to the region of the injection site Immune system disorders: Rare: Hypersensitivity reactions such as, anaphylactic/anaphylactoid reactions including shock, angioneurotic oedema, bronchospasm, dyspnoea, face oedema. Nervous system disorders: Rare: Seizures, including febrile seizures. Gastrointestinal disorders: Very common: Vomiting, diarrhoea, decreased appetite. Skin and subcutaneous tissue disorders: Uncommon: Rash/urticaria. Very rare: Erythema multiforme. General disorders and administration site conditions: Very common: Injection site reactions (e.g. erythema, induration/swelling, pain/tenderness); fever 38 C, irritability, crying, drowsiness, restless sleep. Common: Injection site swelling/induration and erythema >2.4 cm, tenderness interfering with movement, fever > 39 C. Rare: Hypotonic hyporesponsive episode, injection site hypersensitivity reactions (eg., dermatitis, pruritus, urticaria), flushing. Apnoea in very premature infants ( 28 weeks of gestation) (see section 4.4). 4.9 Overdose There have been reports of overdose with Prevenar, including cases of administration of a higher than recommended dose and cases of subsequent doses administered closer than recommended to the previous dose. No undesirable effects were reported in the majority of individuals. In general, adverse reactions reported with overdose have also been reported with recommended single doses of Prevenar. 16

17 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: pneumococcal vaccines, ATC code: J07AL02 Immunogenicity Significant increases in antibody (measured by ELISA) were seen for all vaccine serotypes following a three-dose primary series of Prevenar in infants and following booster doses although geometric mean concentrations varied between the 7 serotypes. Prevenar has also been shown to elicit functional antibodies (measured by opsonophagocytosis) to all vaccine serotypes following the primary series. Longterm persistence of antibodies has not been investigated after administration of a primary series in infants plus booster or after administration of single priming doses to older children. Administration of unconjugated pneumococcal polysaccharides at 13 months following the primary series with Prevenar elicited an anamnestic antibody response for the 7 serotypes included in the vaccine, indicating that priming had occurred. The immunogenicity of a two-dose primary series in infants plus a booster at about one year of age has been documented in several studies. Most of the data have indicated that smaller proportions of infants achieved antibody concentrations 0.35 μg/ml (the reference antibody concentration recommended by WHO) 2 against serotypes 6B and 23F after two-dose primary series when directly or indirectly compared with three-dose primary series. In addition, GMCs were lower for antibodies to most serotypes after a twodose infant series than after a three-dose infant series. However, antibody responses to booster doses in toddlers following two-dose or three-dose infant series were comparable for all 7 vaccine serotypes and indicated that both infant regimens had elicited adequate priming. Significant increases in antibody (measured by ELISA) to all vaccine serotypes were seen after administration of single doses of Prevenar to children aged 2 to 5 years. Antibody concentrations were similar to those achieved following a three-dose infant series and a booster dose at less than 2 years of age. Efficacy trials in the 2- to 5-year-old population have not been conducted. Clinical trial efficacy of the two-dose infant primary series plus a booster has not been established, and the clinical consequences of lower antibody concentrations against serotypes 6B and 23F after the two-dose infant series are not known. Efficacy against invasive disease Estimates of efficacy against invasive disease were obtained in the US population where vaccine serotype coverage ranged from 80 to 89 %. Epidemiological data between 1988 and 2003 indicated that in Europe coverage is lower and varies from country to country. Consequently, Prevenar should cover between 54 % and 84 % of isolates from invasive pneumococcal disease (IPD) in European children less than 2 years of age. In European children between 2 to 5 years of age, Prevenar should cover about 62 % to 83 % of the clinical isolates responsible for invasive pneumococcal disease. It is estimated that more than 80 % of the antimicrobial resistant strains would be covered by the serotypes included in the vaccine. The vaccine serotype coverage in the paediatric population decreases with increasing age. The decrease in the incidence of IPD seen in older children may be partly due to naturally acquired immunity. Efficacy against invasive disease was assessed in a large-scale randomised, double-blind, clinical trial in a multiethnic population in Northern California (Kaiser Permanente trial). More than 37,816 infants were immunised with either Prevenar or a control vaccine (meningococcal conjugate group C vaccine), at 2, 4, 2 WHO technical report No 927, 2005; Appendix serological criteria for calculation and licensure of new pneumococcal conjugate vaccine formulations for use in infants. 17

18 6 and months of age. At the time of the study, the serotypes included in the vaccine accounted for 89 % of IPD. A total of 52 cases of invasive disease caused by vaccine serotypes had accumulated in a blinded followup period through April 20, The estimate of vaccine serotype specific efficacy was 94 % (95 % CI: 81, 99) in the intent-to-treat population and 97 % (95 % CI: 85, 100) in the per protocol (fully immunised) population (40 cases). In Europe, the estimates of effectiveness in children less than 2 years of age range from 51 % to 79 % when considering vaccine coverage against serotypes causing invasive disease. Efficacy against pneumonia In the Kaiser Permanente trial, efficacy was 87.5 % (95 % CI: 7, 99) against bacteraemic pneumonia due to vaccine serotypes of S. pneumoniae. Effectiveness (no microbiological confirmation of diagnosis was performed) against non-bacteraemic pneumonia was also assessed. As many pathogens other than pneumococcal serotypes represented in the vaccine may contribute to the burden of pneumonia in children, protection against all clinical pneumonia is expected to be lower than for invasive pneumococcal disease. In the per-protocol analysis, the estimated risk reduction for the first episode of clinical pneumonia with abnormal chest radiograph (defined as the presence of infiltrates, effusion or consolidation) was 35 % (95 % CI: 4, 56). Efficacy against otitis media Acute otitis media (AOM) is a common childhood disease with different aetiologies. Bacteria can be responsible for 60-70% of clinical episodes of AOM. The pneumococcus is responsible for 30-40% of all bacterial AOM and a greater fraction of severe AOM. Theoretically, Prevenar could prevent about 60-80% of serotypes causing pneumococcal AOM. It is estimated that Prevenar could prevent 6-13% of all clinical episodes of AOM. Efficacy of Prevenar against acute otitis media (AOM) was assessed in a randomised, double blind, clinical trial of 1,662 Finnish infants immunised with either Prevenar or a control vaccine (Hepatitis B vaccine), at 2, 4, 6 and months of age. The estimate for vaccine efficacy against vaccine-serotype AOM, the primary endpoint of the trial, was 57 % (95 % CI: 44, 67) in the per-protocol analysis and 54 % (95 % CI: 41, 64) in the intent-to-treat analysis. A 33 % (95 % CI: -1, 80) increase in AOM due to serogroups not included in the vaccine was observed in immunised subjects. However, the overall benefit was a 34 % (95 % CI: 21, 45) reduction in the incidence of all pneumococcal AOM. The impact of the vaccine on total number of episodes of otitis media regardless of etiology was a 6 % (95 % CI: -4, 16) reduction. A subset of children in this study were followed until they reached 4 to 5 years of age. In this follow-up, vaccine efficacy for frequent OM (defined as at least 3 episodes within 6 months) was 18 % (95 % CI: 1, 32), for chronic otitis media with effusion, 50 % (95 % CI: 15, 71), and for tympanostomy tube placement, 39 % (95 % CI: 4, 61). Efficacy of Prevenar against AOM was assessed as a secondary endpoint in the Kaiser Permanente trial. Children were followed until 3.5 years of age. The impact of the vaccine on total number of episodes of otitis media regardless of etiology was a 7 % reduction (95 % CI: 4, 10). The effect of the vaccine in the per-protocol analysis was a 9 % reduction (95 % CI: 3, 15) in recurrent AOM (defined as 3 episodes in six months or 4 episodes in one year) or a 23 % (95 % CI: 7,36) reduction for recurrent AOM (5 episodes in six months or 6 episodes in one year). Tympanostomy tube placement was reduced by 24 % (95 % CI: 12, 35) in the per-protocol analysis and by 23 % (95 % CI: 11, 34) in the intent-to-treat analysis. 18

19 Effectiveness The effectiveness of Prevenar against IPD (i.e. comprising the protection afforded by vaccination and from herd immunity due to reduced transmission of vaccine serotypes in the population) has been evaluated in national immunisation programmes that employ three-dose or two-dose infant series, each with booster doses. In the USA, generalised vaccination with Prevenar using a four-dose series in infants and a catch-up programme for children up to 5 years of age was introduced in Vaccine effectiveness against IPD caused by vaccine serotypes was evaluated in 3- to 59-month old children within the first four years of the implementation of the programme. When compared with no vaccination, point estimates for the effectiveness of 2-, 3-, or 4-doses given on an infant schedule were similar: 96% (95% CI 88-99); 95% (95% CI 88-99); and 100% (95% CI ), respectively. In the USA in the same time frame, there was a 94% reduction in vaccine type IPD in individuals under 5 years of age, compared to a pre-vaccine baseline (1998/99). In parallel, there was a 62% reduction in vaccine type IPD in individuals over 5 years of age. This indirect or herd effect is due to a reduction in transmission of vaccine serotypes from immunised young children to the rest of the population and coincides with decreased nasopharyngeal carriage of vaccine serotypes. In Quebec, Canada Prevenar was introduced at 2, 4 and 12 months of age with a single dose catch-up programme in children up to 5 years of age. In the first two years of the programme, with over 90% coverage, the observed effectiveness against IPD caused by vaccine serotypes was 93% (95% CI 75-98) for the 2 dose infant series and 100% (95% CI ) for the completed schedule. Preliminary data from England and Wales reported less than 1 year following introduction of routine immunisation at 2, 4 and 13 months with a single dose catch-up programme for children 13 to 23 months of age have suggested that effectiveness of this schedule might be lower against serotype 6B than against the other serotypes in the vaccine. The effectiveness of a two-dose primary series has not been established against pneumonia or acute otitis media. Additional immunogenicity data The immunogenicity of Prevenar has been investigated in an open-label, multicenter study in 49 infants with sickle cell disease. Children were vaccinated with Prevenar (3 doses one month apart from the age of 2 months) and 46 of these children also received a 23-valent pneumococcal polysaccharide vaccine at the age of months. After primary immunisation, 95.6% of the subjects had antibody levels of at least 0.35 µg/ml for all seven serotypes found in Prevenar. A significant increase was seen in the concentrations of antibodies against the seven serotypes after the polysaccharide vaccination, suggesting that immunological memory was well established. 5.2 Pharmacokinetic properties Not applicable 5.3 Preclinical safety data A repeated dose intramuscular toxicity study (13 weeks, 5 injections, one every three weeks) of pneumococcal conjugate vaccine in rabbits revealed no evidence of any significant local or systemic toxic effects. 19